ER stress intoroduce an innovative therapy for metastatic breast cancer.

• Project/Area Number: 26670589
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Tokyo Medical University
• Principal Investigator: Komatsu Seiichiro 東京医科大学, 医学部, 兼任助教 (40408208)
• Co-Investigator(Kenkyū-buntansha): 宮澤 啓介 東京医科大学, 医学部, 主任教授 (50209897)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: オートファジー / 乳癌 / 小胞体ストレス / アグリソーム / プロテアソーム / アポトーシス / リソソーム / 微小管 / アグリゾーム

Outline of Final Research Achievements

As ubiquitinated (Ub) proteins are concentrated at the aggresome upon proteasome failure, we focused on the microtubule as the scaffold of this transport pathway for aggresome formation. Treatment of metastatic breast cancer cell lines with a proteasome inhibitor bortezomib (BZ) resulted in induction of aggresome in a perinuclear lesion. Vinorelbine (VNR), which inhibits microtubule polymerization, more effectively suppressed BZ-induced aggresome formation than paclitaxel (PTX), which stabilizes microtubules. Combined treatment using BZ and VNR, but not PTX, enhanced apoptosis induction along with pronounced ER stress. The addition of azithromycin to block autophagy flux in the BZ plus VNR-containing cell culture further enhanced the cytotoxicity. These data suggest that suppression of BZ-induced aggresome formation using an inhibitory drug such as VNR for microtubule polymerization is a novel strategy for metastatic breast cancer therapy.

Research Products

• [Journal Article] Macrolide antibiotics exhibit cytotoxiceffect under amino acid-depleted culture condition by blocking autophagy flux in head and neck squamous cell carcinoma cell lines. (2016)
  • Author(s): Hirasawa K, Moriya S, Miyahara K, Kazama H, Hirota A, Takemura J, Abe A, Inazu M, Hiramoto M, Tsukahara K, Miyazawa K.
  • Journal Title: PLoS One Volume: 11 Issue: 12 Pages: 1848-1858
  • DOI: 10.1371/journal.pone.0164529
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress-mediated cell death in multiple myeloma cells. (2015)
  • Author(s): Moriya S, Komatsu S, Yamasaki K, Kawai Y, Kokuba H, Hirota A, Che XF, Inazu M, Gotoh A, Hiramoto M, Miyazawa K
  • Journal Title: Int J Oncol. Volume: Feb;46(2) Issue: 2 Pages: 474-86
  • DOI: 10.3892/ijo.2014.2773
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Vinorelbine enhances bortezomib-induced cytotoxic effect via blocking aggresome formation in breast cancer cell lines. (2016)
  • Author(s): Miyahara K, Moriya S, Komatsu S, Hirasawa K, Abe A, Hiramoto M, Ishikawa T, Miyazawa K
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Vinorelbine enhances BZ-induced cytotoxic effect via blocking aggresome formation in breast cancer cell lines (2016)
  • Author(s): Ｍｉｙａｈａｒａ Ｋ， Komatsu S, et al.
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER-stress loading in breast cancer cell lines (2016)
  • Author(s): 宮原か奈、小松誠一郎、風間宏美、森谷昇太、廣田綾子、武村淳、阿部晃久、平本正樹、平澤一浩、國場寛子、石川孝、宮澤啓介
  • Organizer: 第177回東京医科大学医学会総会
  • Place of Presentation: 東京
• [Remarks] 東京医科大学 分子標的センター
  • URL: http://www.tokyo-med.ac.jp/target/
• [Remarks] 東京医科大学 分子標的探索センター
  • URL: http://www.tokyo-med.ac.jp/target/